title: Subclassification and individual survival time prediction from gene expression data of neuroblastoma patients by using CASPAR.
abstract: OBJECTIVE
  To predict individual survival times for neuroblastoma patients from gene expression data using the cancer survival prediction using automatic relevance determination (CASPAR) algorithm.
  
  
  METHODS
  A first set of oligonucleotide microarray gene expression profiles comprising 256 neuroblastoma patients was generated. Then, CASPAR was combined with a leave-one-out cross-validation to predict individual times for both the whole cohort and subgroups of patients with unfavorable markers, including stage 4 disease (n = 67), unfavorable genetic alterations, intermediate-risk or high-risk stratification by the German neuroblastoma trial, and patients predicted as unfavorable by a recently described gene expression classifier (n = 83). Prediction accuracy of individual survival times was assessed by Kaplan-Meier analyses and time-dependent receiver operator characteristics curve analyses. Subsequently, classification results were validated in an independent cohort (n = 120).
  
  
  RESULTS
  CASPAR separated patients with divergent outcome in both the initial and the validation cohort [initial set, 5y-OS 0.94 +/- 0.04 (predicted long survival) versus 0.38 +/- 0.17 (predicted short survival), P < 0.0001; validation cohort, 5y-OS 0.94 +/- 0.07 (long) versus 0.40 +/- 0.13 (short), P < 0.0001]. Time-dependent receiver operator characteristics analyses showed that CASPAR-predicted individual survival times were highly accurate (initial set, mean area under the curve for first 10 years of overall survival prediction 0.92 +/- 0.04; validation set, 0.81 +/- 0.05). Furthermore, CASPAR significantly discriminated short (<5 years) from long survivors (>5 years) in subgroups of patients with unfavorable markers with the exception of MYCN-amplified patients (initial set). Confirmatory results with high significance were observed in the validation cohort [stage 4 disease (P = 0.0049), NB2004 intermediate-risk or high-risk stratification (P = 0.0017), and unfavorable gene expression prediction (P = 0.0017)].
  
  
  CONCLUSIONS
  CASPAR accurately forecasts individual survival times for neuroblastoma patients from gene expression data.
authors.affiliation: Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany. andre.oberthuer@uk-koeln.de
authors.forename: André
authors.initials: A
authors.lastname: Oberthuer
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kahlert
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.forename: Frank
authors.initials: F
authors.lastname: Berthold
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
mesh_terms: D000293:Adolescent; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D000071447:N-Myc Proto-Oncogene Protein; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality*; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D015996:Survival Rate; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm